The neurobiological bases for the transition from occasional to compulsive drug intake remain largely unknown. Mounting evidence points to a key role for neurocircuits involving the hypothalamus in the drug-induced dysregulations that drive compulsive drug taking and relapse after abstinence. Work during the previous (first) funding period uncovered gene expression evidence of remodeling of intrinsic lateral hypothalamic (LH) circuitry in rats with an escalated pattern of cocaine intake. Among the genes affected by cocaine self-administration in the LH was syndecan-3, a hypothalamic proteoglycan previously implicated in feeding. To test the role of syndecan-3 in cocaine escalation we have adapted to the mouse the extended access paradigm previously optimized only for the rat. With this model, we observed that syndecan-3 null mice self- administered more cocaine than wild-type mice and that transgenic mice with ectopic expression in the hypothalamus of a constitutive active allele were resistant to escalating cocaine intake under extended access conditions. These findings suggest that syndecan-3-mediated signaling in the LH is a novel pathway contributing to compulsive drug intake. Building on the results of the previous funding period, the purpose of this proposal is to develop a mechanistic understanding of the role of hypothalamic syndecan-3 in the development of escalated cocaine self-administration. To this aim we propose to investigate regulators and targets of syndecan-3 and the gene networks in which they are active using genomics, mutant mice, biochemical, morphological and behavioral strategies. Collectively, these studies will provide novel information regarding the role of LH dysregulation in the development of compulsive cocaine intake. PUBLIC HEALTH RELEVANCE: The abuse of cocaine and other drugs is epidemic in our society. Research toward a better understanding of the neurobiological bases of drug addiction is necessary to guide the development of pharmacotherapeutic agents for the treatment of drug abuse. Results of the previous funding period suggest the hypothesis that the dysregulation of a specific lateral hypothalamic cellular signaling system may be key in the development of escalated cocaine intake. To extend these results, this proposal is aimed at the exploration of this molecular system and its role in the regulation of cocaine intake. The proposed research will deepen our understanding of the neurobiology of cocaine abuse and may reveal new testable pathogenetic hypotheses and novel therapeutic targets for compulsive drug taking and relapse after cessation.